APO E Receptors and Modulation of Fast Axonal Transport

APO E 受体和快速轴突运输的调节

• 批准号: 7026938
• 负责人: Joachim J Herz
• 金额: $ 36.18万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026938
• 关键词: apolipoprotein E; axon; dynein ATPase; enzyme activity; gene targeting; genetically modified animals; intracellular transport; kinesin; laboratory mouse; mutant; neuronal transport; protein transport; receptor; synapses

DESCRIPTION (provided by applicant): Members of the low-density-lipoprotein (LDL) receptor gene family have recently been found to participate in signal transduction pathways during the development of the brain. Reelin, a large secreted protein that bears no resemblance to lipoproteins and is not involved in lipid transport, binds to the extracellular domains of two members of this gene family, termed VLDL receptor (VLDLR) and ApoE receptor 2 (ApoER2). Binding of this ligand activates a cytoplasmic signaling cascade that apparently involves tyrosine kinases as well as the serine/threonine kinases Cdk5 and GSK-3beta. Disruption of this pathway results in abnormal phosphorylation of the microtubule-associated protein tau and therefore is likely to impair axonal transport processes, which are dependent on the normal function of microtubules. ApoER2 and VLDLR both are expressed abundantly on the surface of embryonic neurons as well as on neurons in the mature brain, where they can also function as receptors for Apolipoprotein E (ApoE). ApoE exists in three major isoforms. One of these isoforms, ApoE4 is genetically associated with late-onset Alzheimer disease. The biochemical basis by which ApoE4 predisposes its carriers to late-onset Alzheimer disease is poorly understood. We hypothesize that ApoE4 acts as a competitor for signaling molecules such as Reelin and reduces their binding to the receptors on the neuronal surface, thereby impairing physiological signaling pathways that regulate neuronal transport and synaptic protein transport. This model would provide a mechanistic basis on which the loss of synapses, which correlates with dementia and precedes the formation of plaques and neurofibrillary tangles, could be explained. The goal of the current proposal is to elucidate the cytoplasmic signaling pathways that are activated by the binding of Reelin to its receptors on the neuronal cell surface and to study the effect of Reelin on axonal transport, the activity of molecular motors such as dynein and kinesin, and the transport of synaptic proteins to their target sites.

描述（由申请人提供）： 低密度脂蛋白（LDL）受体基因家族的成员最近发现 被发现参与信号转导途径 大脑的发育。 Reelin，一种大型分泌蛋白，不具有 与脂蛋白相似，不参与脂质转运，与 该基因家族两个成员的胞外结构域，称为 VLDL 受体 (VLDLR) 和 ApoE 受体 2 (ApoER2)。该配体的结合激活 显然涉及酪氨酸激酶的细胞质信号级联 以及丝氨酸/苏氨酸激酶 Cdk5 和 GSK-3beta。破坏这个 途径导致微管相关的异常磷酸化 tau 蛋白，因此可能会损害轴突运输过程，这 依赖于微管的正常功能。 ApoER2 和 VLDLR 都是 在胚胎神经元表面以及神经元上大量表达 在成熟的大脑中，它们也可以充当受体 载脂蛋白 E (ApoE)。 ApoE 存在三种主要亚型。其中之一 ApoE4 与迟发性阿尔茨海默病有遗传相关性。 ApoE4 使其携带者易患迟发型的生化基础 人们对阿尔茨海默病知之甚少。我们假设 ApoE4 作为 信号分子（如 Reelin）的竞争者，并减少其与 神经元表面的受体，从而损害生理 调节神经元运输和突触蛋白的信号通路 运输。该模型将为损失提供一个机制基础。 突触，与痴呆相关并先于斑块形成 和神经原纤维缠结，可以解释。当前的目标 提议是阐明被激活的细胞质信号传导途径 通过 Reelin 与其神经元细胞表面受体的结合 研究Reelin对轴突运输的影响，分子活性 动力蛋白和驱动蛋白等马达，以及突触蛋白的运输 他们的目标网站。